10-07-2012, 12:42 AM
Parkinson’s disease (PD) is a common neurodegenerative disorder that will assume increasing clinical importance in an ageing society, with an average age of onset between 60 and 65 years, but a peak incidence is found between the ages of 70 and 79 years. The specific incidence is dependent on the age structure of the population studied and is difficult to assess precisely but is around 17 per 100,000 according to a systematic review in this area.
The use of gene therapy to treat PD necessitates the use of a suitable method of delivery for the synthesised nucleic acid—viral or nonviral. The choice of vector greatly influences the technique used for delivery, as a peripherally administered vector must be able to cross the blood-brain barrier with an acceptable degree of tissue specificity. Alternatively, the surgical techniques used for deep brain stimulation can be harnessed to deliver the vector directly to a specific brain region.Nonviral techniques are technically and conceptually more straightforward but are less well suited to treating a chronic neurodegenerative disorder such as PD, due to the short duration of gene expression that is typically achieved. Low transfection rates mean that experiments using nonviral vectors have often used multiple dose regimens. This poses particular problems for translation to human studies if repeated intracerebral injections, with their associated risks, are needed to achieve a meaningful clinical response. This approach may still prove effective, as seen in a recent study using the human glial cell-derived neurotrophic factor (GDNF) gene and a neurotensin polyplex nanoparticle vector in an animal model of PD, finding that a single intracerebral injection of the agent may prove sufficient to induce a biochemical and functional response. Other nonviral vector studies in animal models of PD have incorporated region-specific ligands in order to maximise tissue specificity using intravenous vector administration. For example, one group has used Trojan horse liposomes and a monoclonal antibody to the transferrin receptor to facilitate transport across the blood brain barrier of a peripherally administered therapeutic plasmid containing DNA for GDNF. They also incorporated the gene promoter for tyrosine hydroxylase (TH), a key enzyme in the synthesis of dopamine, to restrict expression of the transgene to catecholaminergic neurons.Viral vectors, derived from either DNA or RNA viral vectors, are generally considered to be a more practical approach, with the potential to cause long lasting gene expression via episome formation or DNA integration into the host genome. A range of different types of viruses, each with different properties and advantages, have been exploited in the search for a suitable vector for gene therapy in PD. These are detailed below, with particular attention to adeno-associated viruses which comprise by far the largest category of vectors used in clinical trials to date.
The use of gene therapy to treat PD necessitates the use of a suitable method of delivery for the synthesised nucleic acid—viral or nonviral. The choice of vector greatly influences the technique used for delivery, as a peripherally administered vector must be able to cross the blood-brain barrier with an acceptable degree of tissue specificity. Alternatively, the surgical techniques used for deep brain stimulation can be harnessed to deliver the vector directly to a specific brain region.Nonviral techniques are technically and conceptually more straightforward but are less well suited to treating a chronic neurodegenerative disorder such as PD, due to the short duration of gene expression that is typically achieved. Low transfection rates mean that experiments using nonviral vectors have often used multiple dose regimens. This poses particular problems for translation to human studies if repeated intracerebral injections, with their associated risks, are needed to achieve a meaningful clinical response. This approach may still prove effective, as seen in a recent study using the human glial cell-derived neurotrophic factor (GDNF) gene and a neurotensin polyplex nanoparticle vector in an animal model of PD, finding that a single intracerebral injection of the agent may prove sufficient to induce a biochemical and functional response. Other nonviral vector studies in animal models of PD have incorporated region-specific ligands in order to maximise tissue specificity using intravenous vector administration. For example, one group has used Trojan horse liposomes and a monoclonal antibody to the transferrin receptor to facilitate transport across the blood brain barrier of a peripherally administered therapeutic plasmid containing DNA for GDNF. They also incorporated the gene promoter for tyrosine hydroxylase (TH), a key enzyme in the synthesis of dopamine, to restrict expression of the transgene to catecholaminergic neurons.Viral vectors, derived from either DNA or RNA viral vectors, are generally considered to be a more practical approach, with the potential to cause long lasting gene expression via episome formation or DNA integration into the host genome. A range of different types of viruses, each with different properties and advantages, have been exploited in the search for a suitable vector for gene therapy in PD. These are detailed below, with particular attention to adeno-associated viruses which comprise by far the largest category of vectors used in clinical trials to date.
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